Reconceptualization of translocator protein as a biomarker of neuroinflammation in psychiatry

Abstract

A great deal of interest in psychiatric research is currently centered upon the pathogenic role of inflammatory processes. Positron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) has become the most widely used technique to assess putative neuroimmune abnormalities in vivo. Originally used to detect discrete neurotoxic damages, TSPO has generally turned into a biomarker of 'neuroinflammation' or 'microglial activation'. Psychiatric research has mostly accepted these denotations of TSPO, even if they may be inadequate and misleading under many pathological conditions. A reliable and neurobiologically meaningful diagnosis of 'neuroinflammation' or 'microglial activation' is unlikely to be achieved by the sole use of TSPO PET imaging. It is also very likely that the pathological meanings of altered TSPO binding or expression are disease-specific, and therefore, not easily generalizable across different neuropathologies or inflammatory conditions. This difficulty is intricately linked to the varying (and still ill-defined) physiological functions and cellular expression patterns of TSPO in health and disease. While altered TSPO binding or expression may indeed mirror ongoing neuroinflammatory processes in some cases, it may reflect other pathophysiological processes such as abnormalities in cell metabolism, energy production and oxidative stress in others. Hence, the increasing popularity of TSPO PET imaging has paradoxically introduced substantial uncertainty regarding the nature and meaning of neuroinflammatory processes and microglial activation in psychiatry, and likely in other neuropathological conditions as well. The ambiguity of conceiving TSPO simply as a biomarker of 'neuroinflammation' or 'microglial activation' calls for alternative interpretations and complimentary approaches. Without the latter, the ongoing scientific efforts and excitement surrounding the role of the neuroimmune system in psychiatry may not turn into therapeutic hope for affected individuals.

TSPO expression and brain structure in the psychosis spectrum

“…However, we measured brain TSPO density which was shown to be independent from inflammatory markers such as cytokines in the periphery or cerebrospinal fluid 9, 63 . Moreover, recent studies suggest that alteration of TSPO expression may also reflect other abnormalities including change in metabolism at the cellular level and oxidative stress 64–66 .…”

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…Thus, TSPO PET is sensitive to changes in neuroinflammatory state. However, TSPO findings are complicated by several factors [87]. First, TSPO levels do not differentiate pro- versus anti-inflammatory processes [87].…”

“…However, TSPO findings are complicated by several factors [87]. First, TSPO levels do not differentiate pro- versus anti-inflammatory processes [87]. Elevated TSPO levels in this context may reflect an upregulation in either pro- or anti-inflammatory processes or both, or leukocyte infiltration.…”

“…Conversely, diminished TSPO levels likely reflect a suppressed/impaired neuroimmune system and/or loss of cells expressing TSPO. Second, TSPO is not functionally involved in neuroimmune signaling (reviewed in [87]). Third, microglia can exhibit “activated” phenotypes in the absence of neuroimmune activation [88, 89], which may lead to false positives.…”

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study

“…The translocator protein (TSPO) is an 18 kDa protein structure located on the outer mitochondrial membrane. In the brain, TSPO is expressed in microglia, astrocytes, endothelial and smooth muscle cells and even neurons (although in lower levels compared to tissues which are essential for steroid production or lipid storage and metabolism) [1,2]. Although TSPO is present throughout the brain under normal physiological conditions [3][4][5], in vitro studies have shown that TSPO expression increases in response to immune activation [6].…”